The TLR7 Agonist Imiquimod Enhances the Anti-Melanoma Effects of a Recombinant Listeria monocytogenes Vaccine

Division of Dermatology, Department of Medicine and Specialty Training and Advanced Research Program, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1747, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2005; 175(3):1983-90. DOI: 10.4049/jimmunol.175.3.1983
Source: PubMed


Activation of innate immune cells through TLR triggers immunomodulating events that enhance cell-mediated immunity, raising the possibility that ligands to these receptors might act as adjuvants in conjunction with T cell activating vaccines. In this report, topical imiquimod, a synthetic TLR7 agonist, significantly enhanced the protective antitumor effects of a live, recombinant listeria vaccine against murine melanoma. This tumor protective effect was not dependent on direct application to the tumor and was associated with an increase in tumor-associated and splenic dendritic cells. Additionally, the combination of imiquimod treatment with prior vaccination led to development of localized vitiligo. These findings indicate that activation of the innate immune system with TLR ligands stimulates dendritic cell activity resulting in a bypass of peripheral tolerance and enhanced antitumor activity. The results of these studies have broad implications for future designs of immunotherapeutic vaccines against tumors and the treatment of metastatic melanoma.

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Available from: Noah Craft, Sep 12, 2014
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    • "An exponential amount of papers are being published emphasizing the enhanced potency of vaccines by incorporating ligands that target TLRs on DCs with antigens, in animal models. TLR2 [10] [11] [12], TLR4 [13] [14] [15] [16] [17] [18], TLR7 [19], TLR8 [20], and TLR9 [21] have been targeted with adjuvants which demonstrated significant antigen-specific enhancement in immune responses as compared to vaccinations without TLR agonists. IFN-gamma is a type II interferon produced by a variety of leukocyte populations including type I helper T (Th1) cells, natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), antigen-presenting cells (APCs) including macrophages and DCs, and B cells. "
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    ABSTRACT: Phenotypic maturation and T cell stimulation are two functional attributes of DCs critical for immune induction. The combination of antigens, including those from cancer, with Toll-like receptor (TLR) ligands induces far superior cellular immune responses compared to antigen alone. In this study, IFN-gamma treatment of bone marrow-derived DC, followed by incubation with the TLR2, TLR4, or TLR9 agonists, enhanced DC activation compared to TLR ligation alone. Most notably, the upregulation of CD40 with LPS stimulation and CD86 with CpG stimulation was observed in in vitro cultures. Similarly, IFN-gamma coinjected with TLR ligands was able to promote DC activation in vivo, with DCs migrating from the site of immunization to the popliteal lymph nodes demonstrating increased expression of CD80 and CD86. The heightened DC activation translated to a drastic increase in T cell stimulatory capacity in both antigen independent and antigen dependent fashions. This is the first time that IFN-gamma has been shown to have a combined effect with TLR ligation to enhance DC activation and function. The results demonstrate the novel use of IFN-gamma together with TLR agonists to enhance antigen-specific T cell responses, for applications in the development of enhanced vaccines and drug targets against diseases including cancer.
    05/2013; 2013:516749. DOI:10.1155/2013/516749
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    • "In addition 1V136 is orally bioavailable, and could potentially be combined with other treatments [5], [34]. The Food and Drug Administration (FDA) has approved topical TLR7 active therapies and experimental systemic treatments have been well tolerated in humans [35], [36], [37], [38], [39], [40], [41]. "
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    ABSTRACT: The Toll-like receptors (TLR) have been advocated as attractive therapeutic targets because TLR signaling plays dual roles in initiating adaptive immune responses and perpetuating inflammation. Paradoxically, repeated stimulation of bone marrow mononuclear cells with a synthetic TLR7 ligand 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (called 1V136) leads to subsequent TLR hyporesponsiveness. Further studies on the mechanism of action of this pharmacologic agent demonstrated that the TLR7 ligand treatment depressed dendritic cell activation, but did not directly affect T cell function. To verify this mechanism, we utilized experimental allergic encephalitis (EAE) as an in vivo T cell dependent autoimmune model. Drug treated SJL/J mice immunized with proteolipid protein (PLP)(139-151) peptide had attenuated disease severity, reduced accumulation of mononuclear cells in the central nervous system (CNS), and limited demyelination, without any apparent systemic toxicity. Splenic T cells from treated mice produced less cytokines upon antigenic rechallenge. In the spinal cords of 1V136-treated EAE mice, the expression of chemoattractants was also reduced, suggesting innate immune cell hyposensitization in the CNS. Indeed, systemic 1V136 did penetrate the CNS. These experiments indicated that repeated doses of a TLR7 ligand may desensitize dendritic cells in lymphoid organs, leading to diminished T cell responses. This treatment strategy might be a new modality to treat T cell mediated autoimmune diseases.
    PLoS ONE 09/2012; 7(9):e45860. DOI:10.1371/journal.pone.0045860 · 3.23 Impact Factor
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    • "Cells were initially gated on live cells area by FSC x SSC analysis, then gated the CD3 positive/CD8 positive/Thy1.1 positive (staining for pmel-1 T cells), followed by TGFβ RII levels analysis. Intracellular IFN-γ staining was done as described previously [22]. Briefly, 1million cells were stimulated with 1 μM specific peptide (gp100(25–33)) or non-relevant peptide Ovalbumin, plus brefeldin A (BD Pharmingen) and 50 U/ml IL-2, for six hours at 37°C in 5% CO2. "
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    ABSTRACT: Tumor antigen-reactive T cells must enter into an immunosuppressive tumor microenvironment, continue to produce cytokine and deliver apoptotic death signals to affect tumor regression. Many tumors produce transforming growth factor beta (TGFbeta), which inhibits T cell activation, proliferation and cytotoxicity. In a murine model of adoptive cell therapy, we demonstrate that transgenic Pmel-1 CD8 T cells, rendered insensitive to TGFbeta by transduction with a TGFbeta dominant negative receptor II (DN), were more effective in mediating regression of established B16 melanoma. Smaller numbers of DN Pmel-1 T cells effectively mediated tumor regression and retained the ability to produce interferon-gamma in the tumor microenvironment. These results support efforts to incorporate this DN receptor in clinical trials of adoptive cell therapy for cancer.
    Journal of Translational Medicine 06/2012; 10(1):127. DOI:10.1186/1479-5876-10-127 · 3.93 Impact Factor
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